title: Multiple (familial) trichoepitheliomas: a clinicopathological and molecular biological study, including CYLD and PTCH gene analysis, of a series of 16 patients.
abstract: Multiple familial trichoepitheliomas (MFT) constitute an autosomally inherited syndrome possibly related to Brooke-Spiegler syndrome (BSS). Although some early studies suggested a role for the PTCH gene on chromosome 9q22.3 in the etiopathogenesis of MFT, recent studies of occasional patients with the MFT clinical phenotype identified mutations in the CYLD gene on chromosome 16q12-q13, a gene responsible for BSS. A systematic investigation of PTCH and CYLD mutations in patients with MFT has never been performed. Our main objective was to collect a reasonably large series of patients with MFT to (1) study the clinicopathological spectrum of the disease, (2) determine whether the PTCH gene is implicated in the pathogenesis of MFT, and if so (3) determine the relative frequency of CYLD and PTCH mutations, (4) establish if there may be any possible genotype-phenotype correlations, and (5) study the spectrum of somatic mutations. Clinical analysis including family histories, histopathological investigations, and molecular genetic studies were performed. There were 9 female and 7 male patients ranging in age from 11 to 63 years. They presented with multiple, small, discrete and sometimes confluent, skin-colored to pink, asymptomatic nodules preferentially located on the face, being especially prominent and confluent in the nasolabial folds and inner aspects of the eyebrows. A total of 66 conventional trichoepitheliomas (TEs) were studied microscopically. Aside from typical features of TE, some also exhibited variant morphological patterns including areas reminiscent of other benign adnexal neoplasms and melanocytic hyperplasia. In none of the 9 patients tested was a germline mutation of the PTCH gene identified. Germline CYLD mutations were detected in 6 of 13 patients tested (identical in 2 unrelated patients) including 2 novel mutations, whereas the remaining 7 individuals showed wild-type alleles. Two patients with germline wild-type CYLD showed, however, a somatic mutation in the gene (1 duplication, 1 substitution mutation). Neither CYLD nor PTCH germline mutations were found in the 5 patients in whom both genes were analyzed. MFT seems to be a phenotypic variant of BSS. The PTCH gene is rarely, if ever, involved in the pathogenesis of MFT. Absence of a germline mutation of the CYLD gene in cases harboring a somatic mutation may be explained by large deletions in the gene or by mutation in intronic sequences or in the promoter region. Considering our 5 patients with no mutation in either gene, the final possibility is that another, as yet undescribed gene (neither CYLD nor PTCH) is implicated in the pathogenesis of some patients with MFT.
authors.affiliation: Sikl's Department of Pathology, Charles University Medical Faculty Hospital, Alej Svobody 80, Pilsen, Czech Republic. kazakov@medima.cz
authors.forename: Dmitry V
authors.initials: DV
authors.lastname: Kazakov
authors.forename: Tomas
authors.initials: T
authors.lastname: Vanecek
authors.forename: Bernhard
authors.initials: B
authors.lastname: Zelger
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Carlson
authors.forename: Dominic V
authors.initials: DV
authors.lastname: Spagnolo
authors.forename: Jörg
authors.initials: J
authors.lastname: Schaller
authors.forename: Jana
authors.initials: J
authors.lastname: Nemcova
authors.forename: Denisa
authors.initials: D
authors.lastname: Kacerovska
authors.forename: Marina
authors.initials: M
authors.lastname: Vazmitel
authors.forename: Martin
authors.initials: M
authors.lastname: Sangüeza
authors.forename: Michael
authors.initials: M
authors.lastname: Emberger
authors.forename: Irena
authors.initials: I
authors.lastname: Belousova
authors.forename: Maria Tereza
authors.initials: MT
authors.lastname: Fernandez-Figueras
authors.forename: Maria Tereza
authors.initials: MT
authors.lastname: Fernandez-Figueraz
authors.forename: Werner
authors.initials: W
authors.lastname: Kempf
authors.forename: Dale R
authors.initials: DR
authors.lastname: Meyer
authors.forename: Arno
authors.initials: A
authors.lastname: Rütten
authors.forename: Mehmet
authors.initials: M
authors.lastname: Baltaci
authors.forename: Michal
authors.initials: M
authors.lastname: Michal
mesh_terms: D000293:Adolescent; D000328:Adult; D018280:Carcinoma, Skin Appendage / Q000235:genetics* / Q000473:pathology; D002648:Child; D004252:DNA Mutational Analysis; D000074749:Deubiquitinating Enzyme CYLD; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009386:Neoplastic Syndromes, Hereditary / Q000235:genetics / Q000473:pathology; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D016133:Polymerase Chain Reaction; D011956:Receptors, Cell Surface / Q000235:genetics*; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface; D025521:Tumor Suppressor Proteins; C409984:CYLD protein, human; D000074749:Deubiquitinating Enzyme CYLD